HPV Vaccination: A Shot of Prevention

Human papillomavirus (HPV) is a common sexually-transmitted infection with the potential for serious morbidity. About 40 strains of HPV can infect the genital areas of men and women. Certain high-risk strains that cause cervical dysplasia and cancer have been identified, whereas other strains cause anogenital warts.

Cervical cancer is the second most common cancer in women worldwide, with an estimated 510,000 cases diagnosed and 288,000 deaths reported annually. Research has shown that nearly all cases of cervical cancers are due to infection with specific carcinogenic strains of HPV; recent advances in vaccination have taken steps toward preventing this cancer.1

HPV Infection

HPV types 16 and 18 are 2 carcinogenic strains associated with about 70% of cervical cancers.1 Other strains associated with cervical cancers are HPV 31, 33, 35, 45, 51, 52, 56, 58, 59, and 68.2 Although screening tests can determine if a patient has been infected with HPV, no commercially available test is able to determine which individual strain is responsible for the infection.

An estimated 90% of anogenital warts result from infection with HPV types 6 and 11. Although these lesions are benign, their eradication may require multiple treatment sessions, with severe cases occasionally requiring surgery for adequate removal of the lesions.1

Not all HPV strains are associated with cancer.3 In many cases, the body clears the infection. In other cases, the HPV infection persists, leading to low- or high-grade dysplasia. These dysplastic lesions may persist and may progress to invasive cancer.1

Preventive Treatment: HPV Vaccination

Globally, 2 HPV vaccines are available: a quadrivalent recombinant vaccine that targets HPV types 6, 11, 16, and 18 (Gardasil), and an AS04 adjuvant-adsorbed bivalent vaccine that targets HPV types 16 and 18 (Cervarix). For maximal efficacy, either vaccine should be given to patients who have not yet become sexually active to ensure that the patient has not yet been exposed to HPV.

Gardasil was evaluated in 2 multicenter, multicountry, double-blind, placebo-controlled clinical trials (Females United to Unilaterally Reduce Endo/EctocervicalDisease [FUTURE] I and FUTURE II). Both trials consisted of women aged 15 to 26, and followed the participants for 3 years after treatment with Gardasil to monitor for the development of high-grade dysplasia. In women who had not been exposed to HPV, Gardasil was found to be 100% (FUTURE I) and 98% (FUTURE II) effective. When the results included all women, regardless of previous HPV exposure, the rate of efficacy decreased.2

Whereas these results indicate that efficacy increases in patients who have not yet been exposed to HPV, there may still be a long-term benefit in vaccination despite previous HPV exposure. When followed for >18 months, women already infected with HPV who received Gardasil had a lower incidence of developing cervical intraepithelial neoplasia than those given the placebo.2

Neither HPV vaccine should be used to treat existing HPV infection. One phase 3 trial studied the use of a bivalent HPV-16/18 vaccine with AS04 in 2189 women aged 18 to 25 who had tested positive for cervical HPV infection. The study's goal was to determine if vaccine administration would increase the rate of HPV clearance. The authors concluded that administration of the vaccine to women already infected with the virus did not increase the rate of clearance, nor should it be used to treat preexisting infections.4

Gardasil in the United States

Currently, Gardasil is the only HPV vaccine approved for use in the United States. The quadrivalent HPV vaccine is recommended for women between ages 9 and 26 for the prevention of certain cancerous and precancerous lesions caused by HPV types 6, 11, 16, and 18 (Table).

The intramuscular injection is given at months 0, 2, and 6 and should not be given to patients with a history of hypersensitivity to any of its components. The vaccine should not be used as treatment for patients with preexisting infection or lesions. The most commonly reported side effects included pain, swelling, erythema, pruritus, and fever. Gardasil should not be used during pregnancy.5

Gardasil will not protect against strains other than the 4 it includes. About 30% of cervical cancers are caused by HPV strains other than those included in the vaccine; as a result, women should continue to have regular Pap tests performed even after completion of the vaccination series.

Each injection of Gardasil costs $125 per dose, and the full series costs $375.6 HPV vaccination is covered by Vaccines for Children, a federal program that provides free vaccination to children under age 19 who are uninsured, Medicaid-eligible, American Indian, or Alaska Native.3

Pending FDA Approval: Cervarix

Cervarix, an AS04 adjuvant-adsorbed bivalent HPV-16/18 vaccine, is not available in the United States, but has been approved in 67 countries across the globe and is currently seeking approval in the United States.7,8

The manufacturer of Cervarix has submitted a biologics license application (BLA) to the FDA. The BLA data consist of clinical trials in nearly 30,000 ethnically diverse girls and women ranging from 10 to 55 years of age, along with results from the largest phase 3 cervical cancer vaccine efficacy trial so far, which took place worldwide in >18,000 young women aged 15 to 25.9

Cervarix consists of the proprietary adjuvant system AS04. AS04 is a compound containing aluminum hydroxide, a traditional adjuvant, and monophosphoryl lipid A, an immunomodulator. When compared with traditional vaccine adjuvants, AS04 is promoted to enhance immune response and in--crease duration of protection.9

Cervarix does not include protection from HPV types 6 and 11 and thus would not be expected to provide protection against anogenital warts. Its use is currently promoted in a wider age range of women; in Australia, the vaccine is indicated for women up to age 45.10

Future Research

Currently, Gardasil is only approved for use in girls and women; the BLA filed for Cervarix is based on data from female patients. It is expected that vaccination in men and boys would prevent anogenital warts and penile or anal cancer, along with minimizing transmission of the virus. Research in vaccination of male patients is still under way.

The length of immunity from the vaccine is still undetermined. Clinical trials followed patients for 5 years and found the vaccine to still be providing immunity at that time. Further research is being completed to determine if a booster will be necessary in the future.3

HPV infection can lead to devastating outcomes. Recent medical advances have taken a proactive stance on HPV infection and its resulting complications. By focusing on prevention at an early age, the HPV vaccine aims to minimize the potential for the adverse outcomes of HPV infection.

GlaxoSmithKline responds to FDA on Cervarix and plans to submit final study data for approval [press release]. www.gsk.com/media/pressreleases/2008/2008_pressrelease_10073.htm. Accessed December 2008.

Cervarix, the GSK cervical cancer candidate vaccine, provides sustained immune response in 100 per cent of women up to 55 years of age [press release].www.gsk.com/media/pressreleases/2007/2007_06_05_GSK1058.htm. Accessed March 2008.

Cervarixnow available for women over 26 years.www.ausbiotech.org/data/downloads/Medical%20media%20release.pdf. Accessed March 2008.